Project Summary Metabolic reprogramming plays a critical role in carcinogenesis, in part due its ability to promote immune suppressive properties within tumors. However, it is unclear whether inhibition of fatty acid metabolism in tumors affects their immunogenicity. Here, we show for the first time that inhibition of stearoyl CoA desaturase 1 (SCD1), the rate limiting enzyme involved in fatty-acid synthesis converting saturated acids (SFA) to monounsaturated fatty acids (MUFAs) and a potential prognostic marker for human cancers, increases the immunogenicity of poorly immunogenic tumors. Our results indicate that inhibition of tumorigenic de novo lipogenesis represents a novel approach to enhance T cell based cancer immunotherapy. In so doing, we will evaluate our novel lead SCD1 inhibitor (SSI-4) singly, and in combination with immune checkpoint inhibitors using immune competent mouse models, as a prelude to an early phase clinical trial. We will also optimize efficacy and seek predictive biomarkers of response that could be clinically useful. SCD1 is universally upregulated in aggressive cancers and validated by SSI-4 antitumor activity across a broad range of cancer cell lines and tumor mouse models. Mechanistically, MUFA deprivation in addicted cancer cells leads to endoplasmic reticulum (ER) stress mediating apoptotic cell death. We discovered in immune competent mouse cancer models that SSI-4 activates the adaptive immune response via calreticulin/PERK arm of the ER stress pathway enhancing activated T cell tumor infiltration and thereby promoting anti-PD1 antibody therapy. Combined with anti-PD1 inhibitor, SSI-4 sensitizes tumors to immune checkpoint inhibitors leading to 80% and 30% complete regression (CR) and long-term survival interpreted as cures in two HER2 breast cancer mouse models. Based upon these data, our central hypothesis is that aberrant de novo lipogenesis is linked to attenuation of tumor immunogenicity. Two aims are proposed in this Phase 2 STTR proposal. Aim 1 will validate antitumor synergy of SCD1 and immune checkpoint blockade using immune competent breast mouse models to generalize the observed data to. Aim 2 is focused upon filing an application for investigation of new drug (IND) for FDA approval in which the following tasks will be accomplished; i) determine SSI-4 compound stability ii) perform non-GLP toxicity studies in rats and dogs iii) convene a pre-IND meeting with the FDA to discuss regulatory strategy iv) perform GLP toxicity studies, v) design the phase I clinical trial and vi) complete the IND application. In summary, we envision SCD1 as a broad spectrum anti-cancer target overexpressed in aggressive malignancies. Therapeutically useful, SSI-4 increases the immunogenicity of poorly immunogenic tumors thereby sensitizing to immune checkpoint blockade, leading to dramatic adaptive immune mediated tumor cell killing. Thus, this combination therapy should enhance patient response rates and be well tolerated in patients.